A head-to-head evaluation of the effect of ramipril and zofenopril on the cardiovascular mortality rate of patients with chronic heart failure (HF) in the setting of clinical practice is not yet available. We prospectively enrolled 224 patients with all-cause HF, who were untreated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. These patients were then assigned to zofenopril 15 to 30 mg/day or ramipril 5 to 10 mg/day on the basis of a prospective, randomized, open, blinded, end point trial. The primary outcome of the trial was patient survival during the follow-up period. The groups were similar in a large number of clinical parameters. The mean follow-up of this cohort was 6.1 ± 1.2 years. Overall, during the follow-up period, we observed 45 deaths in the zofenopril-treated group and 48 in the ramipril-treated group (p = 0.251). Zofenopril and ramipril appears to be equivalent regarding the effects on cardiovascular mortality in the entire sample. Zofenopril was a significant predictor of better survival in patients who were the median age or older (odds ratio 0.56, 95% confidence interval 0.35 to 0.91), in men (odds ratio 0.57, 95% confidence interval 0.30 to 0.98), and in patients with a lower ejection fraction (odds ratio 0.52, 95% confidence interval 0.26 to 0.97). In conclusion, in the clinical practice setting, ramipril and zofenopril seem to have similar effects on cardiovascular mortality. However zofenopril might be more efficacious in elderly patients, male patients, and patients with a lower ejection fraction. Copyright © 2013 Elsevier Inc. All rights reserved.